Microemulsion preconcentrate

ABSTRACT

A microemulsion preconcentrate is provided, which comprises an active component, an oil, a surfactant, and a hydrophilic solvent selected from the group consisting of propylene glycol diacetate, propylene glycol monoacetate, and salts of the forgoing materials.

TECHNICAL FIELD

The present invention relates to a microemulsion preconcentrate.

BACKGROUND ART

Microemulsions are used as solubilizing formulation for hydrophobicdrugs poorly soluble in water. Oil-in-water (O/W) microemulsions aredifficult to commercially produce because its external phase is waterand its stability during shelf-life does not reach a desired level. Forthis reason, drug-containing capsulated microemulsion preconcentratesconsisting of a hydrophilic phase, a lipophilic phase, and a surfactanthave often been used. After oral administration, the capsulatedmicroemulsion preconcentrate is disintegrated and dissolved by a gastricjuice to form microemulsion.

Examples of microemulsion preconcentrates include Sandimmun Neoral™carrying cyclosporin, a widely known hydrophobic drug, which isdisclosed in EP520949A1 (Novartis), Cardus marianus extract or Silibin,which is disclosed in U.S. 2001/005726AA and an oral microemulsioncomposition containing biphenyl dimethyl dicarboxylate as an activecomponent, which is disclosed in Korean Laid-Open Publication No.1998-083257.

However, the microemulsion preconcentrates disclosed in the abovepatents are only for carrying hydrophobic drugs, not for hydrophilicdrugs or protein drugs, and thus have limited applications.

The manufacture of drugs with such microemulsion preconcentrates islimited by the choice of their hydrophilic phase. For example, propyleneglycol, polyethylene glycol, or ethanol, if used for the hydrophilicphase, may vaporize or may interact with and be absorbed into a gelatinshell of a soft capsule over time during capsulation, thereby changingthe original composition of the microemulsion, and eventually leading toprecipitation and separation of the drug. In particular, ethanol mayvaporize completely over time.

Soft capsules lose their shape due to a reaction of their gelatin shellwith the hydrophilic phase of the microemulsion during capsulation, andthe contents leak through gaps in a seam, thereby lowering the yield.During processes of drying and aging soft capsules, an irreversiblesolvent substitution between the moisture in the gelatin shell and thehydrophilic phase of the microemulsion, and migration of othercomponents, occur, thereby greatly changing the original composition ofthe hydrophilic phase in the microemulsion. As a result, the drug isseparated to destroy the microemulsion system. These adverse phenomenacontinue to appear through the shelf-life, making it difficult to massproduce and mass market drug microemulsions.

DISCLOSURE OF THE INVENTION

The present invention provides a microemulsion preconcentrate capable ofdelivering hydrophilic and protein drugs as well as hydrophobic drugs,and having no interaction with a gelatin shell during capsulation tothus secure the stability of the product.

According to one aspect of the invention, there is provided amicroemulsion preconcentrate comprising: an active component; an oil; asurfactant; and a hydrophilic solvent selected from the group consistingof propylene glycol diacetate, propylene glycol monoacetate, and saltsof the forgoing materials.

In the microemulsion preconcentrate according to the present invention,preferably, the ratio by weight of the sum of oil, hydrophilic solvent,and surfactant to the active component is 0.5-10. It is preferable thatthe ratio by weight of oil, hydrophilic solvent, and surfactant is0.5-60: 0.5-60:0.5-80. More preferably, the ratio by weight of oil,hydrophilic solvent, and surfactant is 5-30: 5-30: 5-60.

The microemulsion preconcentrate according to the present invention mayfurther comprise a pharmaceutically acceptable additive. Thepharmaceutically acceptable additive may be at least one selected fromthe group consisting of an antioxidant, a thickening agent, apreservative, and a flavoring agent.

The present invention provides an oral pharmaceutical preparationcomprising the microemulsion preconcentrate. The oral pharmaceuticalpreparation may be any dosage forms for example, soft capsules,gelatin-sealed hard capsules, or liquid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents the granularity distribution result of a microemulsioncomposition diluted with water from a cyclosporin microemulsionpreconcentrate formulated according to Example 1-a; and

FIG. 2 shows photographs of soft capsules: one filled with composition(B) according to example 1-a according to the present invention and theother filled with conventional composition (A), wherein both capsuleswere exposed to the air for 30 days after capsulation.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

A microemulsion preconcentrate according to the present inventionbasically comprises a base compositon including a hydrophilic solvent,an oil, and a surfactant, and a pharmaceutically active component. Thepharmaceutical active component is mixed with and dissolved in the basecomposition to yield the microemulsion preconcentrate. The hydrophilicsolvent is propylene glycol diacetate, propylene glycol monoacetate, ora salt of the forgoing materials. These hydrophilic solvents may bemixed in any combination.

Propylene glycol diacetate, amphipathic solvent for both hydrophobicdrugs, such as cyclosporin, and hydrophilic drugs, has a molecularweight of about 160 and a boiling point of 186° C., so it is lessvolatile at room temperature and less reactive with a gelatin capsuleshell as compared with conventionally used propylene glycol or ethanol.Accordingly, propylene glycol diacetate is suitable for the hydrophilicsolvent.

In the microemulsion preconcentrate according to the present invention,preferably, the ratio by weight of a base compositon including ahydrophilic solvent, an oil, and a surfactant to the active component is0.5-10. It is preferable that the ratio by weight of oil, hydrophilicsolvent, and surfactant is 0.5-60: 0.5-60:0.5-80. More preferably, theratio by weight of oil, hydrophilic solvent, and surfactant is 5-30:5-30: 5-60.

The microemulsion preconcentrate according to the present invention mayfurther include pharmaceutically acceptable additives, such as anantioxidant, a thickening agent, a preservative, a dissolutionregulator, a flavoring agent, a coloring agent, and the like. Forexample, antioxidants may include tocopherols and salts thereof;thickening agents may include polymers, such as hydroxypropyl cellulose,hydroxypropylmethylcellulose, methylcellulose, and Eudragit™; flavoringagents may include apple, pineapple flavors, and the like; andpreservatives may include benzoic acid.

Pharmaceutically acceptable active components for the microemulsionpreconcentrate according to the present invention may include, but arenot limited to: anti-inflammatory agents and anodynes, such aspiroxicam, ketorolac, ketopropen, acetaminophen, aceclofenac, naproxen,gabapentin, and the like; anti-hypertensive drugs, such as amlodipine,felodipine, enalapril, isosorbide dinitrate, terazocine, carvedilol,nifedipine, captopril, and the like; antifungal agents, such asitraconazole, fluconazole, ketoconazole, and the like; anticancer drugs,such as fluorouracil, paclitaxel, adriamycin, and the like; steroiddrugs, such as estradiol, progestin, testosterone, and the like;erectile dysfunction drugs, such as alprostadil; anti-Alzheimer drugs,such as donepezil, rivastigmine, physostigmine, adrenol, and the like;anti-osteoporesis drugs, such as alendronate; immunizing agents, such ascyclosporin, tacrolimus, and the like; antiemetic agents, such asondansetron, scopolamine, meclizine, and the like; tranquilizers, suchas fluoxetine, venlafaxine, and the like; and pharmaceuticallyacceptable salts of the forgoing drugs.

The microemulsion preconcentrate according to the present invention mayinclude, as the active component, not only the above-listed syntheticdrugs, peptide, and hormonal drugs, but also recombinant protein drugs,such as human insulin, human growth hormones, erythropoietin, humanepidermal cell growth factor, and the like.

A suitable surfactant for the microemulsion preconcentrate according tothe present invention may be at least one of, but is not limited to,polyoxyethylene glycolated natural or hydrogenated vegetable oils,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acidesters, polyoxyethylene-polyoxypropylene copolymers, dioctylsuccinate,dioctylsodium sulfosuccinate, di-[α-ethylhexyl]-succinate or sodiumlaurylsulfate, phospholipids, phospholipid derivatives, polyethyleneglycol mono- and di-fatty acid esters, bile acids, bile salts,trans-esterification products of natural vegetable oil triglycerides andpolyalkylene polyols, esterification products of caprylic or capric acidwith glycerol, sorbitan fatty acid esters, pentaerythrite fatty acidesters and pentaerythritol fatty acid esters, polyalkylene glycolethers, polyethylene glycol 660 12-hydroxy stearate, tocopherylpolyethylene glycol 1000 succinate, and cholesterols and derivativesthereof.

Polyoxyethylene glycolated natural or hydrogenated vegetable oils,reaction products of natural or hydrogenated vegetable oils and ethyleneglycol, are commercially available under the trade names of “CremophorRH 40”, “Cremophor EL”, etc.

Polyoxyethylene sorbitan fatty acid esters are commercially availableunder the trade name “Tween”. Tween 20 and Tween 80 are preferred assurfactants for the microemulsion preconcentrate according to thepresent invention.

Polyoxyethylene fatty acid esters are commercially available under thetrade names of “Myrj” and “Briji.”

Polyoxyethlene-polyoxypropylene copolymers are commercially availableunder the trade names of “Poloxamer” and “Pluronic.”

Examples of polyethylene glycol mono- and di-fatty acid esters includepolyethylene glycol dicaprylate, polyethylene glycol dilaurate,polyethylene glycol hydroxystearate, polyethylene glycol isostearate,polyethylene glycol laurate, polyethylene glycol ricinolate, andpolyethylene glycol stearate.

A representative example of bile acids and bile salts is sodiumtaurocholate.

Trans-esterification products of natural vegetable oil triglycerides andpolyalkylene polyols are commercially available under the trade name of“Labrafil”. Labrafil M 1944 CS and “Labrasol” are preferred assurfactants for the microemulsion preconcentrate according to thepresent invention.

Esterification products of caprylic or capric acid with glycerol arecommercially available under the trade name of “Imwitor™”.

Examples of sorbitan fatty acid esters include sorbitan-monolaurylester, sorbitan-monopalmityl ester, sorbitan-monostearyl ester,sorbitan-tristearyl ester, sorbitan-monooleyl ester, andsorbitan-trioleyl ester, which are commercially available under thetrade name of “Span”.

The above-listed surfactants may be used separately alone or in acombination of at least two of the surfactants, with the use of at leasttwo surfactants being preferred.

An example of oil that can be used for the microemulsion preconcentrateaccording to the present invention includes, but is not limited to, atleast one selected from the group consisting of vegetable oils, animaloils, esterification products of vegetable fatty acids, unsaturated longchain fatty acids, esterification products of unsaturated long chainfatty acids, tocopherols, and tocopherol derivatives.

Examples of vegetable oils for the microemulsion preconcentrateaccording to the present invention include corn oil, borage oil, sesameoil, primrose oil, peanut oil, olive oil, and poppy seed oil. Examplesof animal oils include squalenes and omega-3 fatty acids consisting ofeicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Examples of the esterfication products of vegetable oil fatty acidsinclude fatty acid triglycerides, fatty acid mono- and di-glycerides,fatty acid mono- and di-acetylated monoglycerides. Examples ofunsaturated long chain fatty acids include linoleic acid and oleic acid.

Examples of the esterification products of unsaturated long chain fattyacids include ethyl linoleate, ethyl oleate, and ethyl myristate.Examples of tocopherols and derivatives thereof include tocopherolacetates and dl-alpha-tocopherol.

The above-listed oils may be used separately alone or in a combinationof at least two of the oils.

The microemulsion preconcentrate is used for preparing an oralpharmaceutical preparation by conventional methods known in the field.The pharmaceutical preparation may have diverse dosage forms, examplesoft capsules, gelatin-sealed hard capsules, or liquid. For example, apharmaceutically active component is dissolved in a hydrophilic solventunder mild heating. An oil and a surfactant are added into the mixtureand homogeneously mixed, and if necessary, a pharmaceutically acceptableadditive is added into the mixture. The final composition is processedinto soft capsules using a soft-capsule manufacturing machine.

The present invention will be described in greater detail with referenceto the following examples. The following examples are for illustrativepurposes and are not intended to limit the scope of the invention.

EXAMPLE 1 Manufacture of Cyclosporin Microemulsion Preconcentrate andSoft Capsules

100 g of cyclosporin, an active component, was dissolved in ahydrophilic solvent containing 10 g of propylene glycol monoacetate and150 g of propylene glycol diacetate under heating with stirring. 50 g ofPeceol, 60 g of Capmul, and 130 g of Labrafac as oils, and 350 g ofCremphor RH 40 and 200 g of Labrasol as surfactatnts were added into thesolution and mixed by stirring to yield a homogeneous microemulsionpreconcentrate. The resulting microemulsion preconcentrate was pouredinto a soft capsule manufacturing machine and shaped into soft capsulesaccording to general procedures widely used in the field. Each capsulecontained 100 mg of cyclosporin.

Soft capsules of different microemulsion preconcentrate compositions, asshown in Table 1 below, were manufactured for Examples 1-a, 1-b, and 1c, using the same method as described above. TABLE 1 units: grams Exam-Exam- Exam ple ple ple Component Example 1 1-a 1-b 1-c HydrophilicPropyleneglycol 150 225 120 250 solvent diacetate Propyleneglycol 100 —— — monoacetate Surfactant Cremophor RH 40 350 450 400 450 Tween 20 —120 —  50 Labrasol 200 — 150 — Oil Peceol  50 125 — — Capmul MCM  60 —120 — Labrafac CC 130 150 150 — Tocopherol acetate — — — 300 ActiveCyclosporin 100 100 100 100 Component

EXAMPLES 2 to 5 Manufacture of Microemulsion Preconcentrates of VariousDrugs and Soft Capsules

Microemulsion preconcentrates of various drugs, having the compositionsshown in Table 2 below, were prepared, and soft capsules of themicroemulsion preconcentrates were manufactured, using the same methodsas described in Example 1. Each capsule contained an effective dose ofthe active component required for a particular therapeutic effect. TABLE2 units: grams Exam- Exam- Exam- Exam- ple ple ple ple Component 2 3 4 5Hydrophilic Propyleneglycol 250 — 150 180 solvent diacetatePropyleneglycol — 200  70 — monoacetate Surfactant Cremophor RH 40 400350 330 — Poloxamer 124 100 — 120 350 Labrafil — 150 — 150 Oil Mivacet 50 120 — — Ethyl linoleate  60 — 120 — Labrafac CC 140 160 150 250Active Ondansetron 100 — — — component Gabapentin — 100 — — Alendronate— — 100 — Venlafaxine — — — 100

EXAMPLES 6 to 8 Manufacture of Microemulsion Preconcentrates of VariousDrugs and Soft Capsules

Microemulsion preconcentrates of various drugs, having the compositionsshown in Table 3 below, were prepared, and soft capsules of themicroemulsion preconcentrates were manufactured, using the same methodsas described in Eexample 1. Each capsule contained an effective dose ofthe active component required for a particular therapeutic effect. TABLE3 units: grams Component Example 6 Example 7 Example 8 HydrophilicPropyleneglycol 150 225 120 solvent diacetate Propyleneglycol 100 — —monoacetate Surfactant Poloxamer 124 400 450 450 Tween 80 100 120 —Labrasol — — 100 Yolk Lecithin — — 150 Oil Ethyl myristate  50  50 —Capmul MCM  50 — 120 Labrafac CC 130 150 — Lipiodol — — 200 ActiveItraconazole 100 — — component Prostaglandin — 100 — Paclitaxel — — 100

EXAMPLES 9 to 11 Manufacture of Microemulsion Preconcentrates of VariousDrugs and Soft Capsules

Microemulsion preconcentrates of various drugs, having the compositionsshown in Table 4 below, were prepared, and soft capsules of themicroemulsion preconcentrates were manufactured, using the same methodsas described in Example 1. Each capsule contained an effective dose ofthe active component required for a particular therapeutic effect. TABLE4 units: grams Component Example 9 Example 10 Example 11 HydrophilicPropyleneglycol 150 225 120 solvent diacetate Propyleneglycol — —  50monoacetate Surfactant Solutol HS 15 200 150 450 Labrasol — —  50 YolkLecithin — — 150 Capmul MCM  50 — 120 Labrafac CC — 150 — Linoleic acid— —  50 Lactic acid 100 —  50 Active Insulin 100 — — Component Human EGF— 100 — hormone Interferon — — 100

EXPERIMENTAL EXAMPLE 1 Granularity Distribution Analysis ofMicroemulsion

After diluting microemulsion preconcentrate manufactured in Example 1-awith water, the granularity distribution of the formed microemulsion wasanalyzed using a Nicomp 380. The results are shown in FIG. 1.

As is evident from FIG. 1, the microemulsion preconcentrate according tothe present invention forms an oil-in-water microemulsion having anaverage particle diameter of 30 nm or less in the internal oil phase.

EXPERIMENTAL EXAMPLE 2 Study on Soft Capsule Deformation

Changes in the shape of soft capsules were observed using themicroemulsion preconcentrate prepared in Example 1-a and theconventional microemulsion preconcentrate prepared according to Example3 of Korean Patent No. 01-31064. After filling empty soft capsules witheach of the microemulsion preconcentrates, the soft capsules were leftexposed to the air for 30 days before observation of the capsuleappearance. As shown in the photographs of the soft capsules of FIG. 2,capsule B filled with the microemulsion preconcentrate according to thepresent invention retains its original shape perfectly, whereas capsuleA filled with the conventional microemulsion preconcentrate is deformeddue to interaction with the gelatin capsule shell.

EXPERIMENTAL EXAMPLE 3 Bioequivalence Test

A bioequivalence test was performed on 6 dogs usingcyclosporin-containing microemulsion soft capsules (test capsules)prepared in Example 1, each capsule containing 100 mg of cyclosporin,and using Sandimmun Neoral of Novartis, reference capsules forcomparison. The bioequivalence test was performed according to a 2×2crossover study design using latin square method. TABLE 5 Phase GroupSubject I II 1 A, B, C Reference Test 2 D, E. F Test Reference

The six dogs were randomly divided into two groups of 3, and werelabeled in alphabetical order. The above soft capsule containing 100 mgof cyclosporin was orally administered to each dog. Between the twotreatments, one-week washout period is proveded. The test animals wereno longer fed starting at noon, the day before the test day. In the testday, test and reference capsules were orally administered to the animalson an empty stomach, and no food or water was supplied for 4 hoursfollowing administration. The animals were fed 4 hours afteradministration.

2 ml of venous blood was collected using heparin-treated syringes fromthe cephatic vein at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 8.0,and 12.0 hours after administration of the test and reference capsules.The collected blood samples were immediately frozen at −60° C. The bloodcyclosporin concentration was measured using radioimmuno assay (RIA).The results are shown in FIG. 3. Paracokinetic parameters of the testand reference capsules were calculated based on the data of FIG. 3. Theresults are shown in Table 6. TABLE 6 Pharmacokinetic parameters of testand reference capsules AUC(hr · ng/ml) C_(max) (ng/ml) T_(max) (hrs)Reference 8290.6 1241.1 1.33 Test 7649.7 1189.9 1.25 % Deviation −7.73%−4.13% −6.25%

As is evident from the Experimental Examples, the microemulsionpreconcentrate according to the present invention forms a stablemicroemulsion with an inner phase particle size of 30 nm or less, andhas low reactivity with a gelatin soft capsule shell. The microemulsionpreconcentrate according to the present invention is able to carryhydrophilic and protein drugs as well as hydrophobic drugs, poorlysoluble in water, and ensures storage stability of the formulationbecause it does not interact with a gelatin capsule shell, duringformulation.

1. A microemulsion preconcentrate comprising: an active component; anoil; a surfactant; and a hydrophilic solvent selected from the groupconsisting of propylene glycol diacetate, propylene glycol monoacetate,and salts of the forgoing materials.
 2. The microemulsion preconcentrateof claim 1, wherein the ratio by weight of the sum of oil, hydrophilicsolvent, and surfactant to the active component is 0.5-10.
 3. Themicroemulsion preconcentrate of claim 1, wherein the ratio by weight ofoil, hydrophilic solvent, and surfactant is 0.5-60: 0.5-60:0.5-80. 4.The microemulsion preconcentrate of claim 1, wherein the activecomponent is selected from the group consisting of piroxicam, ketorolac,ketopropen, acetaminophen, aceclofenac, naproxen, gabapentin,amlodipine, felodipine, enalapril, isosorbide dinitrate, terazocine,carvedilol, nifedipine, captopril, itraconazole, fluconazole,ketoconazole, fluorouracil, paclitaxel, adriamycin, estradiol,progestin, testosterone, alprostadil, donepezil, rivastigmine,physostigmine, adrenol™, alendronate, cyclosporin, tacrolimus,ondansetron, scopolamine, meclizine, fluoxetine, venlafaxine, andpharmaceutically acceptable salts of the forgoing components.
 5. Themicroemulsion preconcentrate of claim 1, wherein the active component iscyclosporin.
 6. An oral pharmaceutical preparation comprising: amicroemulsion preconcentrate including: an active component; an oil; asurfactant; and a hydrophilic solvent selected from the group consistingof propylene glycol diacetate, propylene glycol monoacetate, and saltsof the forgoing materials.
 7. The oral pharmaceutical preparation ofclaim 6, wherein the oral pharmaceutical preparation is soft capsule,gelatin-sealed hard capsule, or liquid.
 8. The oral pharmaceuticalpreparation of claim 6, wherein the ratio by weight of the sum of oil,hydrophilic solvent, and surfactant to the active component is 0.5-10.9. The oral pharmaceutical preparation of claim 6, wherein the ratio byweight of oil, hydrophilic solvent, and surfactant is 0.5-60:0.5-60:0.5-80.
 10. The oral pharmaceutical preparation of claim 6,wherein the active component is selected from the group consisting ofpiroxicam, ketorolac, ketopropen, acetaminophen, aceclofenac, naproxen,gabapentin, amlodipine, felodipine, enalapril, isosorbide dinitrate,terazocine, carvedilol, nifedipine, captopril, itraconazole,fluconazole, ketoconazole, fluorouracil, paclitaxel, adriamycin,estradiol, progestin, testosterone, alprostadil, donepezil,rivastigmine, physostigmine, adrenol™, alendronate, cyclosporin,tacrolimus, ondansetron, scopolamine, meclizine, fluoxetine,venlafaxine, and pharmaceutically acceptable salts of the forgoingcomponents.
 11. The oral pharmaceutical preparation of claim 1, whereinthe active component is cyclosporin.